Neurostimulation titration process via adaptive parametric modification

ABSTRACT

Systems and methods are provided for delivering neurostimulation therapies to patients. A titration process is used to gradually increase the stimulation intensity to a desired therapeutic level. Between titration sessions one or more parameters, such as, for example, an acclimation interval, may be adjusted based on the patient&#39;s response to the stimulation. This personalized titration process can minimize the amount of time required to complete titration so as to begin delivery of the stimulation at therapeutically desirable levels.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/078,600, filed Nov. 12, 2014, the disclosure of which is incorporatedherein by reference in its entirety.

FIELD

This application relates to neuromodulation and, more specifically, toimproved systems and methods for titrating stimulation therapies.

BACKGROUND

Chronic heart failure (CHF) and other forms of chronic cardiacdysfunction (CCD) may be related to an autonomic imbalance of thesympathetic and parasympathetic nervous systems that, if left untreated,can lead to cardiac arrhythmogenesis, progressively worsening cardiacfunction and eventual patient death. CHF is pathologically characterizedby an elevated neuroexitatory state and is accompanied by physiologicalindications of impaired arterial and cardiopulmonary baroreflex functionwith reduced vagal activity.

CHF triggers compensatory activations of the sympathoadrenal(sympathetic) nervous system and the renin-angiotensin-aldosteronehormonal system, which initially helps to compensate for deterioratingheart-pumping function, yet, over time, can promote progressive leftventricular dysfunction and deleterious cardiac remodeling. Patientssuffering from CHF are at increased risk of tachyarrhythmias, such asatrial fibrillation (AF), ventricular tachyarrhythmias (ventriculartachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter,particularly when the underlying morbidity is a form of coronary arterydisease, cardiomyopathy, mitral valve prolapse, or other valvular heartdisease. Sympathoadrenal activation also significantly increases therisk and severity of tachyarrhythmias due to neuronal action of thesympathetic nerve fibers in, on, or around the heart and through therelease of epinephrine (adrenaline), which can exacerbate analready-elevated heart rate.

The standard of care for managing CCD in general continues to evolve.For instance, new therapeutic approaches that employ electricalstimulation of neural structures that directly address the underlyingcardiac autonomic nervous system imbalance and dysregulation have beenproposed. In one form, controlled stimulation of the cervical vagusnerve beneficially modulates cardiovascular regulatory function. Vagusnerve stimulation (VNS) has been used for the clinical treatment ofdrug-refractory epilepsy and depression, and more recently has beenproposed as a therapeutic treatment of heart conditions such as CHF. Forinstance, VNS has been demonstrated in canine studies as efficacious insimulated treatment of AF and heart failure, such as described in Zhanget al., “Chronic Vagus Nerve Stimulation Improves Autonomic Control andAttenuates Systemic Inflammation and Heart Failure Progression in aCanine High-Rate Pacing Model,” Circ Heart Fail 2009, 2, pp. 692-699(Sep. 22, 2009), the disclosure of which is incorporated by reference.The results of a multi-center open-label phase II study in which chronicVNS was utilized for CHF patients with severe systolic dysfunction isdescribed in De Ferrari et al., “Chronic Vagus Nerve Stimulation: A Newand Promising Therapeutic Approach for Chronic Heart Failure,” EuropeanHeart Journal, 32, pp. 847-855 (Oct. 28, 2010).

VNS therapy commonly requires implantation of a neurostimulator, asurgical procedure requiring several weeks of recovery before theneurostimulator can be activated and a patient can start receiving VNStherapy. Even after the recovery and activation of the neurostimulator,a full therapeutic dose of VNS is not immediately delivered to thepatient to avoid causing significant patient discomfort and otherundesirable side effects. Instead, to allow the patient to adjust to theVNS therapy, a titration process is utilized in which the intensity isgradually increased over a period of time under a control of aphysician, with the patient given time between successive increases inVNS therapy intensity to adapt to the new intensity. As stimulation ischronically applied at each new intensity level, the patient's tolerancethreshold, or tolerance zone boundary, gradually increases, allowing foran increase in intensity during subsequent titration sessions. Thetitration process can take significantly longer in practice because theincrease in intensity is generally performed by a physician or otherhealthcare provider, and thus, for every step in the titration processto take place, the patient has to visit the provider's office to havethe titration performed. Scheduling conflicts in the provider's officemay increase the time between titration sessions, thereby extending theoverall titration process, during which the patient in need of VNS doesnot receive the VNS at the full therapeutic intensity.

For patients receiving VNS therapy for the treatment of epilepsy, atitration process that continues over an extended period of time, suchas six to twelve months, may be somewhat acceptable because thepatient's health condition typically would not worsen in that period oftime. However, for patients being treated for other health conditions,such as CHF, the patient's condition may degrade rapidly if leftuntreated. As a result, there is a much greater urgency to completingthe VNS titration process when treating a patient with a time-sensitivecondition, such as CHF.

Accordingly, a need remains for an approach to efficiently titrateneurostimulation therapy for treating chronic cardiac dysfunction andother conditions.

SUMMARY

Systems and methods are provided for delivering neurostimulationtherapies to patients. A titration process is used to gradually increasethe stimulation intensity to a desired therapeutic level. One or moretitration parameters, such as, e.g., an acclimation interval betweentitration sessions, a pulse amplitude, a pulse frequency, a pulse width,and a stimulation duty cycle, may be adjusted based on the patient'sresponse to the stimulation. This personalized titration process canminimize the amount of time required to complete titration so as tobegin delivery of the stimulation at therapeutically desirable levels.The amount of time between titration sessions can be adjusted based onthe patient's actual rate of VNS adaption, instead of initiatingtitration sessions based on a predetermined schedule. Because patientsadapt to VNS stimulation at different rates, a systematic approach totitrating the stimulation parameters can provide a tailored process foreach patient, thereby further reducing the total titration duration forpatients who acclimate to the stimulation at a faster than average rate.

In accordance with embodiments of the present invention, a method ofoperating an implantable medical device (IMD) comprising aneurostimulator coupled to an electrode assembly is provided. The methodcomprises: initiating a plurality of titration sessions, each titrationsession separated from an adjacent titration session by an acclimationinterval, wherein the titration sessions comprise activating the IMD todeliver a stimulation signal of gradually increasing intensity until thepatient exceeds a side effect tolerance zone boundary; analyzing anoutcome measure of the plurality of titration sessions; and modifyingone or more stimulation parameters based on the analyzed outcomemeasure.

Still other embodiments of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription, wherein are described embodiments by way of illustratingthe best mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodimentsand its several details are capable of modifications in various obviousrespects, all without departing from the spirit and the scope of thepresent invention. Accordingly, the drawings and detailed descriptionare to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the implantableneurostimulator and the simulation therapy lead of FIG. 1.

FIG. 3 is a diagram showing an external programmer for use with theimplantable neurostimulator of FIG. 1.

FIG. 4 is a diagram showing electrodes provided as on the stimulationtherapy lead of FIG. 2 in place on a vagus nerve in situ.

FIG. 5 is a graph showing, by way of example, the relationship betweenthe targeted therapeutic efficacy and the extent of potential sideeffects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 6 is a graph showing, by way of example, the optimal duty cyclerange based on the intersection depicted in FIG. 5.

FIG. 7 is a timing diagram showing, by way of example, a stimulationcycle and an inhibition cycle of VNS as provided by implantableneurostimulator of FIG. 1.

FIGS. 8A-8C are illustrative charts reflecting a heart rate response togradually increased stimulation intensity at different frequencies.

FIG. 9 illustrates a method for delivering vagus nerve stimulationtherapy.

FIG. 10 illustrates a titration process in accordance with embodimentsof the present invention.

FIGS. 11A-11B are block diagrams of neurostimulation systems inaccordance with embodiments of the present invention.

FIG. 12 illustrates a titration process with variable titrationparameters in accordance with embodiments of the present invention.

FIGS. 13-17 are flow diagrams illustrating a multi-threaded titrationprocess in accordance with embodiments of the present invention.

DETAILED DESCRIPTION

CHF and other cardiovascular diseases cause derangement of autonomiccontrol of the cardiovascular system, favoring increased sympathetic anddecreased parasympathetic central outflow. These changes are accompaniedby elevation of basal heart rate arising from chronic sympathetichyperactivation along the neurocardiac axis.

The vagus nerve is a diverse nerve trunk that contains both sympatheticand parasympathetic fibers, and both afferent and efferent fibers. Thesefibers have different diameters and myelination, and subsequently havedifferent activation thresholds. This results in a graded response asintensity is increased. Low intensity stimulation results in aprogressively greater tachycardia, which then diminishes and is replacedwith a progressively greater bradycardia response as intensity isfurther increased. Peripheral neurostimulation therapies that target thefluctuations of the autonomic nervous system have been shown to improveclinical outcomes in some patients. Specifically, autonomic regulationtherapy results in simultaneous creation and propagation of efferent andafferent action potentials within nerve fibers comprising the cervicalvagus nerve. The therapy directly improves autonomic balance by engagingboth medullary and cardiovascular reflex control components of theautonomic nervous system. Upon stimulation of the cervical vagus nerve,action potentials propagate away from the stimulation site in twodirections, efferently toward the heart and afferently toward the brain.Efferent action potentials influence the intrinsic cardiac nervoussystem and the heart and other organ systems, while afferent actionpotentials influence central elements of the nervous system.

An implantable vagus nerve stimulator, such as used to treatdrug-refractory epilepsy and depression, can be adapted for use inmanaging chronic cardiac dysfunction (CCD) through therapeuticbi-directional vagus nerve stimulation. FIG. 1 is a front anatomicaldiagram showing, by way of example, placement of an implantable medicaldevice (e.g., a vagus nerve stimulation (VNS) system 11, as shown inFIG. 1) in a male patient 10, in accordance with embodiments of thepresent invention. The VNS provided through the stimulation system 11operates under several mechanisms of action. These mechanisms includeincreasing parasympathetic outflow and inhibiting sympathetic effects byinhibiting norepinephrine release and adrenergic receptor activation.More importantly, VNS triggers the release of the endogenousneurotransmitter acetylcholine and other peptidergic substances into thesynaptic cleft, which has several beneficial anti-arrhythmic,anti-apoptotic, and anti-inflammatory effects as well as beneficialeffects at the level of the central nervous system.

The implantable vagus stimulation system 11 comprises an implantableneurostimulator or pulse generator 12 and a stimulating nerve electrodeassembly 125. The stimulating nerve electrode assembly 125, preferablycomprising at least an electrode pair, is conductively connected to thedistal end of an insulated, electrically conductive lead assembly 13 andelectrodes 14. The electrodes 14 may be provided in a variety of forms,such as, e.g., helical electrodes, probe electrodes, cuff electrodes, aswell as other types of electrodes.

The implantable vagus stimulation system 11 can be remotely accessedfollowing implant through an external programmer, such as the programmer40 shown in FIG. 3 and described in further detail below. The programmer40 can be used by healthcare professionals to check and program theneurostimulator 12 after implantation in the patient 10 and to adjuststimulation parameters during the initial stimulation titration process.In some embodiments, an external magnet may provide basic controls, suchas described in commonly assigned U.S. Pat. No. 8,600,505, entitled“Implantable Device For Facilitating Control Of Electrical StimulationOf Cervical Vagus Nerves For Treatment Of Chronic Cardiac Dysfunction,”the disclosure of which is incorporated by reference. For furtherexample, an electromagnetic controller may enable the patient 10 orhealthcare professional to interact with the implanted neurostimulator12 to exercise increased control over therapy delivery and suspension,such as described in commonly-assigned U.S. Pat. No. 8,571,654, entitled“Vagus Nerve Neurostimulator With Multiple Patient-Selectable Modes ForTreating Chronic Cardiac Dysfunction,” the disclosure of which isincorporated by reference. For further example, an external programmermay communicate with the neurostimulation system 11 via other wired orwireless communication methods, such as, e.g., wireless RF transmission.Together, the implantable vagus stimulation system 11 and one or more ofthe external components form a VNS therapeutic delivery system.

The neurostimulator 12 is typically implanted in the patient's right orleft pectoral region generally on the same side (ipsilateral) as thevagus nerve 15, 16 to be stimulated, although otherneurostimulator-vagus nerve configurations, including contra-lateral andbi-lateral are possible. A vagus nerve typically comprises two branchesthat extend from the brain stem respectively down the left side andright side of the patient, as seen in FIG. 1. The electrodes 14 aregenerally implanted on the vagus nerve 15, 16 about halfway between theclavicle 19 a-b and the mastoid process. The electrodes may be implantedon either the left or right side. The lead assembly 13 and electrodes 14are implanted by first exposing the carotid sheath and chosen branch ofthe vagus nerve 15, 16 through a latero-cervical incision (perpendicularto the long axis of the spine) on the ipsilateral side of the patient'sneck 18. The helical electrodes 14 are then placed onto the exposednerve sheath and tethered. A subcutaneous tunnel is formed between therespective implantation sites of the neurostimulator 12 and helicalelectrodes 14, through which the lead assembly 13 is guided to theneurostimulator 12 and securely connected.

In one embodiment, the neural stimulation is provided as a low levelmaintenance dose independent of cardiac cycle. The stimulation system 11bi-directionally stimulates either the left vagus nerve 15 or the rightvagus nerve 16. However, it is contemplated that multiple electrodes 14and multiple leads 13 could be utilized to stimulate simultaneously,alternatively or in other various combinations. Stimulation may bethrough multimodal application of continuously-cycling, intermittent andperiodic electrical stimuli, which are parametrically defined throughstored stimulation parameters and timing cycles. Both sympathetic andparasympathetic nerve fibers in the vagosympathetic complex arestimulated. A study of the relationship between cardiac autonomic nerveactivity and blood pressure changes in ambulatory dogs is described inJ. Hellyer et al., “Autonomic Nerve Activity and Blood Pressure inAmbulatory Dogs,” Heart Rhythm, Vol. 11(2), pp. 307-313 (February 2014).Generally, cervical vagus nerve stimulation results in propagation ofaction potentials from the site of stimulation in a bi-directionalmanner. The application of bi-directional propagation in both afferentand efferent directions of action potentials within neuronal fiberscomprising the cervical vagus nerve improves cardiac autonomic balance.Afferent action potentials propagate toward the parasympathetic nervoussystem's origin in the medulla in the nucleus ambiguus, nucleus tractussolitarius, and the dorsal motor nucleus, as well as towards thesympathetic nervous system's origin in the intermediolateral cell columnof the spinal cord. Efferent action potentials propagate toward theheart 17 to activate the components of the heart's intrinsic nervoussystem. Either the left or right vagus nerve 15, 16 can be stimulated bythe stimulation system 11. The right vagus nerve 16 has a moderatelylower (approximately 30%) stimulation threshold than the left vagusnerve 15 for heart rate effects at the same stimulation frequency andpulse width.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, lead assembly 13, and electrodes 14. FIGS. 2A and 2B are diagramsrespectively showing the implantable neurostimulator 12 and thestimulation lead assembly 13 of FIG. 1. In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy Demipulse Model 103or AspireSR Model 106 pulse generator, manufactured and sold byCyberonics, Inc., Houston, Tex., although other manufactures and typesof implantable VNS neurostimulators could also be used. The stimulationlead assembly 13 and electrodes 14 are generally fabricated as acombined assembly and can be adapted from a Model 302 lead, PerenniaDURAModel 303 lead, or PerenniaFLEX Model 304 lead, also manufactured andsold by Cyberonics, Inc., in three sizes based, for example, on ahelical electrode inner diameter, although other manufactures and typesof single-pin receptacle-compatible therapy leads and electrodes couldalso be used.

Referring first to FIG. 2A, the system 20 may be configured to providemultimodal vagus nerve stimulation. In a maintenance mode, theneurostimulator 12 is parametrically programmed to delivercontinuously-cycling, intermittent and periodic ON-OFF cycles of VNS.Such delivery produces action potentials in the underlying nerves thatpropagate bi-directionally, both afferently and efferently.

The neurostimulator 12 includes an electrical pulse generator that istuned to improve autonomic regulatory function by triggering actionpotentials that propagate both afferently and efferently within thevagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermeticallysealed housing 21 constructed of a biocompatible material, such astitanium. The housing 21 contains electronic circuitry 22 powered by abattery 23, such as a lithium carbon monofluoride primary battery or arechargeable secondary cell battery. The electronic circuitry 22 may beimplemented using complementary metal oxide semiconductor integratedcircuits that include a microprocessor controller that executes acontrol program according to stored stimulation parameters and timingcycles; a voltage regulator that regulates system power; logic andcontrol circuitry, including a recordable memory 29 within which thestimulation parameters are stored, that controls overall pulse generatorfunction, receives and implements programming commands from the externalprogrammer, or other external source, collects and stores telemetryinformation, processes sensory input, and controls scheduled andsensory-based therapy outputs; a transceiver that remotely communicateswith the external programmer using radio frequency signals; an antenna,which receives programming instructions and transmits the telemetryinformation to the external programmer; and a reed switch 30 thatprovides remote access to the operation of the neurostimulator 12 usingan external programmer, a simple patient magnet, or an electromagneticcontroller. The recordable memory 29 can include both volatile (dynamic)and non-volatile/persistent (static) forms of memory, within which thestimulation parameters and timing cycles can be stored. Other electroniccircuitry and components are possible.

The neurostimulator 12 includes a header 24 to securely receive andconnect to the lead assembly 13. In one embodiment, the header 24encloses a receptacle 25 into which a single pin for the lead assembly13 can be received, although two or more receptacles could also beprovided, along with the corresponding electronic circuitry 22. Theheader 24 internally includes a lead connector block (not shown), asetscrew, and a spring contact (not shown) that electrically connects tothe lead ring, thus completing the electrical circuit 26.

In some embodiments, the housing 21 may also contain a heart rate sensor31 that is electrically interfaced with the logic and control circuitry,which receives the patient's sensed heart rate as sensory inputs. Theheart rate sensor 31 monitors heart rate using an ECG-type electrode.Through the electrode, the patient's heart beat can be sensed bydetecting ventricular depolarization. In a further embodiment, aplurality of electrodes can be used to sense voltage differentialsbetween electrode pairs, which can undergo signal processing for cardiacphysiological measures, for instance, detection of the P-wave, QRScomplex, and T-wave. The heart rate sensor 31 provides the sensed heartrate to the control and logic circuitry as sensory inputs that can beused to determine the onset or presence of arrhythmias, particularly VT,and/or to monitor and record changes in the patient's heart rate overtime or in response to applied stimulation signals.

Referring next to FIG. 2B, the lead assembly 13 delivers an electricalsignal from the neurostimulator 12 to the vagus nerve 15, 16 via theelectrodes 14. On a proximal end, the lead assembly 13 has a leadconnector 27 that transitions an insulated electrical lead body to ametal connector pin 28 and metal connector ring. During implantation,the connector pin 28 is guided through the receptacle 25 into the header24 and securely fastened in place using the setscrew 26 to electricallycouple one electrode of the lead assembly 13 to the neurostimulator 12while the spring contact makes electrical contact to the ring connectedto the other electrode. On a distal end, the lead assembly 13 terminateswith the electrode 14, which bifurcates into a pair of anodic andcathodic electrodes 62 (as further described infra with reference toFIG. 4). In one embodiment, the lead connector 27 is manufactured usingsilicone and the connector pin 28 and ring are made of stainless steel,although other suitable materials could be used, as well. The insulatedlead body 13 utilizes a silicone-insulated alloy conductor material.

In some embodiments, the electrodes 14 are helical and placed around thecervical vagus nerve 15, 16 at the location below where the superior andinferior cardiac branches separate from the cervical vagus nerve. Inalternative embodiments, the helical electrodes may be placed at alocation above where one or both of the superior and inferior cardiacbranches separate from the cervical vagus nerve. In one embodiment, thehelical electrodes 14 are positioned around the patient's vagus nerveoriented with the end of the helical electrodes 14 facing the patient'shead. In an alternate embodiment, the helical electrodes 14 arepositioned around the patient's vagus nerve 15, 16 oriented with the endof the helical electrodes 14 facing the patient's heart 17. At thedistal end, the insulated electrical lead body 13 is bifurcated into apair of lead bodies that are connected to a pair of electrodes. Thepolarity of the electrodes could be configured into a proximal anode anda distal cathode, or a proximal cathode and a distal anode.

The neurostimulator 12 may be interrogated prior to implantation andthroughout the therapeutic period with a healthcare provider-operablecontrol system comprising an external programmer and programming wand(shown in FIG. 3) for checking proper operation, downloading recordeddata, diagnosing problems, and programming operational parameters, suchas described in commonly-assigned U.S. Pat. Nos. 8,600,505 and8,571,654, cited supra. FIG. 3 is a diagram showing an externalprogrammer 40 for use with the implantable neurostimulator 12 of FIG. 1.The external programmer 40 includes a healthcare provider operableprogramming computer 41 and a programming wand 42. Generally, use of theexternal programmer is restricted to healthcare providers, while morelimited manual control is provided to the patient through “magnet mode.”

In one embodiment, the external programmer 40 executes applicationsoftware 45 specifically designed to interrogate the neurostimulator 12.The programming computer 41 interfaces to the programming wand 42through a wired or wireless data connection. The programming wand 42 canbe adapted from a Model 201 Programming Wand, manufactured and sold byCyberonics, Inc., and the application software 45 can be adapted fromthe Model 250 Programming Software suite, licensed by Cyberonics, Inc.Other configurations and combinations of external programmer 40,programming wand 42 and application software 45 are possible.

The programming computer 41 can be implemented using a general purposeprogrammable computer and can be a personal computer, laptop computer,ultrabook computer, netbook computer, handheld computer, tabletcomputer, smart phone, or other form of computational device. In oneembodiment, the programming computer is a tablet computer that mayoperate under the iOS operating system from Apple Inc., such as the iPadfrom Apple Inc., or may operate under the Android operating system fromGoogle Inc., such as the Galaxy Tab from Samsung Electronics Co., Ltd.In an alternative embodiment, the programming computer is a personaldigital assistant handheld computer operating under the Pocket-PC,Windows Mobile, Windows Phone, Windows RT, or Windows operating systems,licensed by Microsoft Corporation, Redmond, Wash., such as the Surfacefrom Microsoft Corporation, the Dell Axim X5 and X50 personal dataassistants, sold by Dell, Inc., Round Top, Tex., the HP Jornada personaldata assistant, sold by Hewlett-Packard Company, Palo Alto, Tex. Theprogramming computer 41 functions through those componentsconventionally found in such devices, including, for instance, a centralprocessing unit, volatile and persistent memory, touch-sensitivedisplay, control buttons, peripheral input and output ports, and networkinterface. The computer 41 operates under the control of the applicationsoftware 45, which is executed as program code as a series of process ormethod modules or steps by the programmed computer hardware. Otherassemblages or configurations of computer hardware, firmware, andsoftware are possible.

Operationally, the programming computer 41, when connected to aneurostimulator 12 through wireless telemetry using the programming wand42, can be used by a healthcare provider to remotely interrogate theneurostimulator 12 and modify stored stimulation parameters. Theprogramming wand 42 provides data conversion between the digital dataaccepted by and output from the programming computer and the radiofrequency signal format that is required for communication with theneurostimulator 12. In other embodiments, the programming computer maycommunicate with the implanted neurostimulator 12 using other wirelesscommunication methods, such as wireless RF transmission. The programmingcomputer 41 may further be configured to receive inputs, such asphysiological signals received from patient sensors (e.g., implanted orexternal). These sensors may be configured to monitor one or morephysiological signals, e.g., vital signs, such as body temperature,pulse rate, respiration rate, blood pressure, etc. These sensors may becoupled directly to the programming computer 41 or may be coupled toanother instrument or computing device which receives the sensor inputand transmits the input to the programming computer 41. The programmingcomputer 41 may monitor, record, and/or respond to the physiologicalsignals in order to effectuate stimulation delivery in accordance withembodiments of the present invention.

The healthcare provider operates the programming computer 41 through auser interface that includes a set of input controls 43 and a visualdisplay 44, which could be touch-sensitive, upon which to monitorprogress, view downloaded telemetry and recorded physiology, and reviewand modify programmable stimulation parameters. The telemetry caninclude reports on device history that provide patient identifier,implant date, model number, serial number, magnet activations, total ONtime, total operating time, manufacturing date, and device settings andstimulation statistics and on device diagnostics that include patientidentifier, model identifier, serial number, firmware build number,implant date, communication status, output current status, measuredcurrent delivered, lead impedance, and battery status. Other kinds oftelemetry or telemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46and the bottom surface 47 of the programming wand 42 is placed on thepatient's chest over the location of the implanted neurostimulator 12. Aset of indicator lights 49 can assist with proper positioning of thewand and a set of input controls 48 enable the programming wand 42 to beoperated directly, rather than requiring the healthcare provider toawkwardly coordinate physical wand manipulation with control inputs viathe programming computer 41. The sending of programming instructions andreceipt of telemetry information occur wirelessly through radiofrequency signal interfacing. Other programming computer and programmingwand operations are possible.

FIG. 4 is a diagram showing the helical electrodes 14 provided as on thestimulation lead assembly 13 of FIG. 2 in place on a vagus nerve 15, 16in situ 50. Although described with reference to a specific manner andorientation of implantation, the specific surgical approach andimplantation site selection particulars may vary, depending uponphysician discretion and patient physical structure.

Under one embodiment, helical electrodes 14 may be positioned on thepatient's vagus nerve 61 oriented with the end of the helical electrodes14 facing the patient's head. At the distal end, the insulatedelectrical lead body 13 is bifurcated into a pair of lead bodies 57, 58that are connected to a pair of electrodes 51, 52. The polarity of theelectrodes 51, 52 could be configured into a proximal anode and a distalcathode, or a proximal cathode and a distal anode. In addition, ananchor tether 53 is fastened over the lead bodies 57, 58 that maintainsthe helical electrodes' position on the vagus nerve 61 followingimplant. In one embodiment, the conductors of the electrodes 51, 52 aremanufactured using a platinum and iridium alloy, while the helicalmaterials of the electrodes 51, 52 and the anchor tether 53 are asilicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 arecoiled around the vagus nerve 61 proximal to the patient's head, eachwith the assistance of a pair of sutures 54, 55, 56, made of polyesteror other suitable material, which help the surgeon to spread apart therespective helices. The lead bodies 57, 58 of the electrodes 51, 52 areoriented distal to the patient's head and aligned parallel to each otherand to the vagus nerve 61. A strain relief bend 60 can be formed on thedistal end with the insulated electrical lead body 13 aligned, forexample, parallel to the helical electrodes 14 and attached to theadjacent fascia by a plurality of tie-downs 59 a-b.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by “magnet mode”), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpreselected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12, suchas described in commonly-assigned U.S. Pat. No. 8,630,709, entitled“Computer-Implemented System and Method for Selecting Therapy Profilesof Electrical Stimulation of Cervical Vagus Nerves for Treatment ofChronic Cardiac Dysfunction,” the disclosure of which is incorporated byreference.

Therapeutically, the VNS may be delivered as a multimodal set oftherapeutic doses, which are system output behaviors that arepre-specified within the neurostimulator 12 through the storedstimulation parameters and timing cycles implemented in firmware andexecuted by the microprocessor controller. The therapeutic doses includea maintenance dose that includes continuously-cycling, intermittent andperiodic cycles of electrical stimulation during periods in which thepulse amplitude is greater than 0 mA (“therapy ON”) and during periodsin which the pulse amplitude is 0 mA (“therapy OFF”).

The neurostimulator 12 can operate either with or without an integratedheart rate sensor, such as respectively described in commonly-assignedU.S. Pat. No. 8,577,458, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction with Leadless Heart Rate Monitoring,” and U.S.patent application, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction,” Ser. No. 13/314,119, filed on Dec. 7, 2011,pending, the disclosures of which are hereby incorporated by referenceherein in their entirety. Additionally, where an integrated leadlessheart rate monitor is available, the neurostimulator 12 can provideautonomic cardiovascular drive evaluation and self-controlled titration,such as respectively described in commonly-assigned U.S. patentapplication entitled “Implantable Device for Evaluating AutonomicCardiovascular Drive in a Patient Suffering from Chronic CardiacDysfunction,” Ser. No. 13/314,133, filed on Dec. 7, 2011, U.S. PatentPublication No. 2013-0158616 A1, pending, and U.S. patent applicationentitled “Implantable Device for Providing Electrical Stimulation ofCervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction withBounded Titration,” Ser. No. 13/314,135, filed on Dec. 7, 2011, U.S.Patent Publication No. 2013-0158617 A1, pending, the disclosures ofwhich are incorporated by reference. Finally, the neurostimulator 12 canbe used to counter natural circadian sympathetic surge upon awakeningand manage the risk of cardiac arrhythmias during or attendant to sleep,particularly sleep apneic episodes, such as respectively described incommonly-assigned U.S. patent application entitled “ImplantableNeurostimulator-Implemented Method For Enhancing Heart Failure PatientAwakening Through Vagus Nerve Stimulation,” Ser. No. 13/673,811, filedon Nov. 9, 2012, U.S. Patent Publication No. 2014-0135864-A1, pending,the disclosure of which is incorporated by reference.

The VNS stimulation signal may be delivered as a therapy in amaintenance dose having an intensity that is insufficient to elicitundesirable side effects, such as cardiac arrhythmias. The VNS can bedelivered with a periodic duty cycle in the range of 2% to 89% with apreferred range of around 4% to 36% that is delivered as a low intensitymaintenance dose. Alternatively, the low intensity maintenance dose maycomprise a narrow range approximately at 17.5%, such as around 15% to25%. The selection of duty cycle is a tradeoff among competing medicalconsiderations. The duty cycle is determined by dividing the stimulationON time by the sum of the ON and OFF times of the neurostimulator 12during a single ON-OFF cycle. However, the stimulation time may alsoneed to include ramp-up time and ramp-down time, where the stimulationfrequency exceeds a minimum threshold (as further described infra withreference to FIG. 7).

FIG. 5 is a graph 70 showing, by way of example, the relationshipbetween the targeted therapeutic efficacy 73 and the extent of potentialside effects 74 resulting from use of the implantable neurostimulator 12of FIG. 1, after the patient has completed the titration process. Thegraph in FIG. 5 provides an illustration of the failure of increasedstimulation intensity to provide additional therapeutic benefit, oncethe stimulation parameters have reached the neural fulcrum zone, as willbe described in greater detail below with respect to FIG. 8. As shown inFIG. 5, the x-axis represents the duty cycle 71. The duty cycle isdetermined by dividing the stimulation ON time by the sum of the ON andOFF times of the neurostimulator 12 during a single ON-OFF cycle.However, the stimulation time may also include ramp-up time andramp-down time, where the stimulation frequency exceeds a minimumthreshold (as further described infra with reference to FIG. 7). Whenincluding the ramp-up and ramp-down times, the total duty cycle may becalculated as the ON time plus the ramp-up and ramp-down times dividedby the OFF time, ON time, and ramp-up and ramp-down times, and may be,e.g., between 15% and 30%, and more specifically approximately 23%. They-axis represents physiological response 72 to VNS therapy. Thephysiological response 72 can be expressed quantitatively for a givenduty cycle 71 as a function of the targeted therapeutic efficacy 73 andthe extent of potential side effects 74, as described infra. The maximumlevel of physiological response 72 (“max”) signifies the highest pointof targeted therapeutic efficacy 73 or potential side effects 74.

Targeted therapeutic efficacy 73 and the extent of potential sideeffects 74 can be expressed as functions of duty cycle 71 andphysiological response 72. The targeted therapeutic efficacy 73represents the intended effectiveness of VNS in provoking a beneficialphysiological response for a given duty cycle and can be quantified byassigning values to the various acute and chronic factors thatcontribute to the physiological response 72 of the patient 10 due to thedelivery of therapeutic VNS. Acute factors that contribute to thetargeted therapeutic efficacy 73 include beneficial changes in heartrate variability and increased coronary flow, reduction in cardiacworkload through vasodilation, and improvement in left ventricularrelaxation. Chronic factors that contribute to the targeted therapeuticefficacy 73 include improved cardiovascular regulatory function, as wellas decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, renin-angiotensin-aldosterone system down-regulation,anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatoryeffects. These contributing factors can be combined in any manner toexpress the relative level of targeted therapeutic efficacy 73,including weighting particular effects more heavily than others orapplying statistical or numeric functions based directly on or derivedfrom observed physiological changes. Empirically, targeted therapeuticefficacy 73 steeply increases beginning at around a 5% duty cycle, andlevels off in a plateau near the maximum level of physiological responseat around a 30% duty cycle. Thereafter, targeted therapeutic efficacy 73begins decreasing at around a 50% duty cycle and continues in a plateaunear a 25% physiological response through the maximum 100% duty cycle.

The intersection 75 of the targeted therapeutic efficacy 73 and theextent of potential side effects 74 represents one optimal duty cyclerange for VNS. FIG. 6 is a graph 80 showing, by way of example, theoptimal duty cycle range 83 based on the intersection 75 depicted inFIG. 5. The x-axis represents the duty cycle 81 as a percentage ofstimulation time over stimulation time plus inhibition time. The y-axisrepresents therapeutic points 82 reached in operating theneurostimulator 12 at a given duty cycle 81. The optimal duty cyclerange 83 is a function 84 of the intersection 75 of the targetedtherapeutic efficacy 73 and the extent of potential side effects 74. Thetherapeutic operating points 82 can be expressed quantitatively for agiven duty cycle 81 as a function of the values of the targetedtherapeutic efficacy 73 and the extent of potential side effects 74 atthe given duty cycle shown in the graph 70 of FIG. 5. The optimaltherapeutic operating point 85 (“max”) signifies a tradeoff that occursat the point of highest targeted therapeutic efficacy 73 in light oflowest potential side effects 74 and that point will typically be foundwithin the range of a 5% to 30% duty cycle 81. Other expressions of dutycycles and related factors are possible.

Therapeutically and in the absence of patient physiology of possiblemedical concern, such as cardiac arrhythmias, VNS is delivered in a lowlevel maintenance dose that uses alternating cycles of stimuliapplication (ON) and stimuli inhibition (OFF) that are tuned to activateboth afferent and efferent pathways. Stimulation results inparasympathetic activation and sympathetic inhibition, both throughcentrally-mediated pathways and through efferent activation ofpreganglionic neurons and local circuit neurons. FIG. 7 is a timingdiagram showing, by way of example, a stimulation cycle and aninhibition cycle of VNS 90, as provided by implantable neurostimulator12 of FIG. 1. The stimulation parameters enable the electricalstimulation pulse output by the neurostimulator 12 to be varied by bothamplitude (output current 96) and duration (pulse width 94). The numberof output pulses delivered per second determines the signal frequency93. In one embodiment, a pulse width in the range of 100 to 250 μsecdelivers between 0.02 mA and 50 mA of output current at a signalfrequency of about 10 Hz, although other therapeutic values could beused as appropriate. In general, the stimulation signal delivered to thepatient may be defined by a stimulation parameter set comprising atleast an amplitude, a frequency, a pulse width, and a duty cycle.

In one embodiment, the stimulation time is considered the time periodduring which the neurostimulator 12 is ON and delivering pulses ofstimulation, and the OFF time is considered the time period occurringin-between stimulation times during which the neurostimulator 12 is OFFand inhibited from delivering stimulation.

In another embodiment, as shown in FIG. 7, the neurostimulator 12implements a stimulation time 91 comprising an ON time 92, a ramp-uptime 97 and a ramp-down time 98 that respectively precede and follow theON time 92. Under this embodiment, the ON time 92 is considered to be atime during which the neurostimulator 12 is ON and delivering pulses ofstimulation at the full output current 96. Under this embodiment, theOFF time 95 is considered to comprise the ramp-up time 97 and ramp-downtime 98, which are used when the stimulation frequency is at least 10Hz, although other minimum thresholds could be used, and both ramp-upand ramp-down times 97, 98 last two seconds, although other time periodscould also be used. The ramp-up time 97 and ramp-down time 98 allow thestrength of the output current 96 of each output pulse to be graduallyincreased and decreased, thereby avoiding deleterious reflex behaviordue to sudden delivery or inhibition of stimulation at a programmedintensity.

Therapeutic vagus neural stimulation has been shown to providecardioprotective effects. Although delivered in a maintenance dosehaving an intensity that is insufficient to elicit undesirable sideeffects, such as cardiac arrhythmias, ataxia, coughing, hoarseness,throat irritation, voice alteration, or dyspnea, therapeutic VNS cannevertheless potentially ameliorate pathological tachyarrhythmias insome patients. Although VNS has been shown to decrease defibrillationthreshold, VNS has not been shown to terminate VF in the absence ofdefibrillation. VNS prolongs ventricular action potential duration, somay be effective in terminating VT. In addition, the effect of VNS onthe AV node may be beneficial in patients with AF by slowing conductionto the ventricles and controlling ventricular rate.

Neural Fulcrum Zone

As described above, autonomic regulation therapy results in simultaneouscreation of action potentials that simultaneously propagate away fromthe stimulation site in afferent and efferent directions within axonscomprising the cervical vagus nerve complex. Upon stimulation of thecervical vagus nerve, action potentials propagate away from thestimulation site in two directions, efferently toward the heart andafferently toward the brain. Different parameter settings for theneurostimulator 12 may be adjusted to deliver varying stimulationintensities to the patient. The various stimulation parameter settingsfor current VNS devices include output current amplitude, signalfrequency, pulse width, signal ON time, and signal OFF time.

When delivering neurostimulation therapies to patients, it is generallydesirable to avoid stimulation intensities that result in eitherexcessive tachycardia or excessive bradycardia. However, researchershave typically utilized the patient's heart rate changes as a functionalresponse indicator or surrogate for effective recruitment of nervefibers and engagement of the autonomic nervous system elementsresponsible for regulation of heart rate, which may be indicative oftherapeutic levels of VNS. Some researchers have proposed that heartrate reduction caused by VNS stimulation is itself beneficial to thepatient.

In accordance with some embodiments, a neural fulcrum zone isidentified, and neurostimulation therapy is delivered within the neuralfulcrum zone. This neural fulcrum zone corresponds to a combination ofstimulation parameters at which autonomic engagement is achieved but forwhich a functional response determined by heart rate change is nullifieddue to the competing effects of afferently and efferently-transmittedaction potentials. In this way, the tachycardia-inducing stimulationeffects are offset by the bradycardia-inducing effects, therebyminimizing side effects such as significant heart rate changes whileproviding a therapeutic level of stimulation. One method of identifyingthe neural fulcrum zone is by delivering a plurality of stimulationsignals at a fixed frequency but with one or more other parametersettings changed so as to gradually increase the intensity of thestimulation.

FIGS. 8A-8C provide illustrative charts reflecting the location of theneural fulcrum zone. FIG. 8A is a chart 800 illustrating a heart rateresponse in response to such a gradually increased intensity at a firstfrequency, in accordance with embodiments of the present invention. Inthis chart 800, the x-axis represents the intensity level of thestimulation signal, and the y-axis represents the observed heart ratechange from the patient's baseline basal heart rate observed when nostimulation is delivered. In this example, the stimulation intensity isincreased by increasing the output current amplitude.

A first set 810 of stimulation signals is delivered at a first frequency(e.g., 10 Hz). Initially, as the intensity (e.g., output currentamplitude) is increased, a tachycardia zone 851-1 is observed, duringwhich period, the patient experiences a mild tachycardia. As theintensity continues to be increased for subsequent stimulation signals,the patient's heart rate response begins to decrease and eventuallyenters a bradycardia zone 853-1, in which a bradycardia response isobserved in response to the stimulation signals. As described above, theneural fulcrum zone is a range of stimulation parameters at which thefunctional effects from afferent activation are balanced with ornullified by the functional effects from efferent activation to avoidextreme heart rate changes while providing therapeutic levels ofstimulation. In accordance with some embodiments, the neural fulcrumzone 852-1 can be located by identifying the zone in which the patient'sresponse to stimulation produces either no heart rate change or a mildlydecreased heart rate change (e.g., <5% decrease, or a target number ofbeats per minute). As the intensity of stimulation is further increasedat the fixed first frequency, the patient enters an undesirablebradycardia zone 853-1. In these embodiments, the patient's heart rateresponse is used as an indicator of autonomic engagement. In otherembodiments, other physiological responses may be used to indicate thezone of autonomic engagement at which the propagation of efferent andafferent action potentials are balanced, the neural fulcrum zone.

FIG. 8B is a chart 860 illustrating a heart rate response in response tosuch a gradually increased intensity at two additional frequencies, inaccordance with embodiments of the present invention. In this chart 860,the x-axis and y-axis represent the intensity level of the stimulationsignal and the observed heart rate change, respectively, as in FIG. 8A,and the first set 810 of stimulation signals from FIG. 8A is also shown.

A second set 810 of stimulation signals is delivered at a secondfrequency lower than the first frequency (e.g., 5 Hz). Initially, as theintensity (e.g., output current amplitude) is increased, a tachycardiazone 851-2 is observed, during which period, the patient experiences amild tachycardia. As the intensity continues to be increased forsubsequent stimulation signals, the patient's heart rate response beginsto decrease and eventually enters a bradycardia zone 853-2, in which abradycardia response is observed in response to the stimulation signals.The low frequency of the stimulation signal in the second set 820 ofstimulation signals limits the functional effects of nerve fiberrecruitment and, as a result, the heart response remains relativelylimited. Although this low frequency stimulation results in minimal sideeffects, the stimulation intensity is too low to result in effectiverecruitment of nerve fibers and engagement of the autonomic nervoussystem. As a result, a therapeutic level of stimulation is notdelivered.

A third set of 830 of stimulation signals is delivered at a thirdfrequency higher than the first and second frequencies (e.g., 20 Hz). Aswith the first set 810 and second set 820, at lower intensities, thepatient first experiences a tachycardia zone 851-3. At this higherfrequency, the level of increased heart rate is undesirable. As theintensity is further increased, the heart rate decreases, similar to thedecrease at the first and second frequencies but at a much higher rate.The patient first enters the neural fulcrum zone 852-3 and then theundesirable bradycardia zone 853-3. Because the slope of the curve forthe third set 830 is much steeper than the second set 820, the region inwhich the patient's heart rate response is between 0% and −5% (e.g., theneural fulcrum zone 852-3) is much narrower than the neural fulcrum zone852-2 for the second set 820. Accordingly, when testing differentoperational parameter settings for a patient by increasing the outputcurrent amplitude by incremental steps, it can be more difficult tolocate a programmable output current amplitude that falls within theneural fulcrum zone 852-3. When the slope of the heart rate responsecurve is high, the resulting heart rate may overshoot the neural fulcrumzone and create a situation in which the functional response transitionsfrom the tachycardia zone 851-3 to the undesirable bradycardia zone853-3 in a single step. At that point, the clinician would need toreduce the amplitude by a smaller increment or reduce the stimulationfrequency in order to produce the desired heart rate response for theneural fulcrum zone 852-3.

FIG. 8C is a chart 880 illustrating mean heart rate response surfaces inconscious, normal dogs during 14 second periods of right cervical vagusVNS stimulation ON-time. The heart rate responses shown in z-axisrepresent the percentage heart rate change from the baseline heart rateat various sets of VNS parameters, with the pulse width the pulse widthset at 250 μsec, the pulse amplitude ranging from 0 mA to 3.5 mA(provided by the x-axis) and the pulse frequency ranging from 2 Hz to 20Hz (provided by the y-axis). Curve 890 roughly represents the range ofstimulation amplitude and frequency parameters at which a null response(i.e., 0% heart rate change from baseline) is produced. This nullresponse curve 890 is characterized by the opposition of functionalresponses (e.g., tachycardia and bradycardia) arising from afferent andefferent activation.

Titration Process

Several classes of implantable medical devices provide therapy usingelectrical current as a stimulation vehicle. When such a systemstimulates certain organs or body structures like the vagus nerve,therapeutic levels of electrical stimulation are usually not welltolerated by patients without undergoing a process known as titration.Titration is a systematic method of slowly increasing, over time,stimulation parameters employed by an implanted device to deliverstimulation current until therapeutic levels become tolerated by thepatient.

FIG. 9 is a flow diagram showing a method for delivering vagus nervestimulation therapy, in accordance with embodiments of the presentinvention. A titration process is used to gradually increase thestimulation intensity to a desired therapeutic level. If the stimulationintensity is increased too quickly before the patient is fullyaccommodated to the stimulation signal, the patient may experienceundesirable side effects, such as coughing, hoarseness, throatirritation, or expiratory reflex. The titration process graduallyincreases stimulation intensity within a tolerable level, and maintainsthat intensity for a period of time to permit the patient to adjust toeach increase in intensity, thereby gradually increasing the patient'sside effect tolerance zone boundary to so as to accommodate subsequentincreases in intensity. The titration process continues until adequateadaptation is achieved. In embodiments, the titration process isautomated and is executed by the implanted device without manualadjustment of the stimulation intensity by the subject or health careprovider. As will be described in greater detail below, adequateadaptation is a composite threshold comprising one or more of thefollowing: an acceptable side effect level, a target intensity level,and a target physiological response. In preferred embodiments, adequateadaption includes all three objectives: an acceptable side effect level,a target intensity level, and a target physiological response.

As described above, it may be desirable to minimize the amount of timerequired to complete the titration process so as to begin delivery ofthe stimulation at therapeutically desirable levels, particularly whenthe patient is being treated for an urgent condition such as CHF. Inaddition, it is desirable to utilize a maintenance dose intensity at theminimum level required to achieve the desired therapeutic effect. Thiscan reduce power requirements for the neurostimulator and reduce patientdiscomfort.

It has been observed that a patient's side effect profile is moresensitive to the stimulation output current than to the otherstimulation parameters, such as frequency, pulse width, and duty cycle.As a result, accommodation to the stimulation output current is aprimary factor in completing the titration process. It has also beenobserved that if the other stimulation parameters are maintained at alevel below the target levels, the output current can be increased tohigher levels without eliciting undesirable side effects that would beresult when the other parameters are at the target level. As a result,increasing the target output current while maintaining the otherstimulation parameters (pulse width in particular) at reduced levels canresult in a faster accommodation and shorter overall titration time thanwould be achieved by attempting to increase the output current whilestimulating at the target pulse width.

In step 901, a stimulation system 11, including a neurostimulator 12, anerve stimulation lead assembly 13, and a pair of electrodes 14, isimplanted in the patient. In step 902, the patient undergoes an optionalpost-surgery recovery period, during which time the surgical incisionsare allowed to heal and no VNS therapy occurs. This period may last,e.g., two weeks post surgery. In step 903, the stimulation therapyprocess is initiated. During this process, VNS therapy is titrated byadjusting one or more of the stimulation parameters, including outputcurrent, pulse width, signal frequency, and duty cycle, as will bedescribed in greater detail below. Completion of the titration processdetermines the stimulation intensity to be used for subsequentmaintenance doses delivered in step 904. These maintenance doses may beselected to provide the minimum stimulation intensity necessary toprovide the desired therapeutic result.

FIG. 10 is a flow diagram illustrating a titration process 1000 inaccordance with embodiments of the present invention. When firstinitiating the titration process, the neurostimulator 11 is configuredto generate a stimulation signal having an initial stimulation parameterset. The initial parameter set may comprise an initial output current,an initial frequency, an initial pulse width, and an initial duty cycle.The various initial parameter settings may vary, but may be selected sothat one or more of the parameters are set at levels below a predefinedtarget parameter set level, such that the titration process is used togradually increase the intensity parameters to achieve adequateadaptation. In some embodiments, the initial frequency is set at thetarget frequency level, while the initial output current, initial pulsewidth, and initial duty cycle are set below their respective targetlevels. In one embodiment, the target parameter set comprises a 10 Hzfrequency, 250 μsec pulse width, a duty cycle of 14 sec ON and 1.1minutes OFF, and an output current of between 1.5 mA-3.0 mA (e.g., 2.5mA for right side stimulation and 3.0 mA for left side stimulation), andthe initial parameter set comprises 10 Hz frequency, 130 μsec pulsewidth, a duty cycle of 14 sec ON and 1.1 minutes OFF, and an outputcurrent of between 0.25 mA-0.5 mA. In other embodiments, the targetparameter set includes a 5 Hz frequency is used instead of a 10 Hzfrequency.

In step 1001, the stimulation system delivers stimulation to thepatient. If this is the first titration session, then the stimulationwould be delivered with the initial stimulation parameter set describedabove. If this is a subsequent titration session, then the stimulationintensity would remain at the same level at the conclusion of theprevious titration session.

In step 1002, the output current is gradually increased until thestimulation results in an intolerable side effect level, the targetoutput current (e.g., 2.5 mA) is reached, or adequate adaptation isachieved. As described above, adequate adaptation is a compositethreshold comprising one or more of the following: an acceptable sideeffect level, a target intensity level, and a target physiologicalresponse. In accordance with some embodiments, the target physiologicalresponse comprises a target heart rate change during stimulation. Thepatient's heart rate may be monitored using an implanted or externalheart rate monitor, and the patient's heart rate during stimulation iscompared to the patient's baseline heart rate to determine the extent ofheart rate change. In accordance with some embodiments, the target heartrate change is a heart rate change of between 4% and 5%. If at any pointduring the titration process 1000 adequate adaptation is achieved, thetitration process ends and the stimulation intensity which resulted inthe adequate adaptation is used for ongoing maintenance dose therapydelivery.

The output current may be increased in any desired increment, but smallincrements, e.g., 0.1 mA or 0.25 mA, may be desirable so as to enablemore precise adjustments. In some cases, the output current incrementsmay be determined by the neurostimulator's maximum control capability.During the initial titration sessions, it is likely that the patient'sside effect tolerance zone boundary will be reached well before theoutput current reaches the target level or adequate adaptation isachieved. At decision step 1003, if the target output current has notbeen achieved but the maximum tolerable side effects have been exceeded,the process proceeds to step 1004.

In step 1004, the output current is reduced one increment to bring theside effects within acceptable levels. In addition, the frequency isreduced. In embodiments in which the initial frequency was 10 Hz, instep 1004, the frequency may be reduced, e.g., to 5 Hz or 2 Hz.

Next, in step 1005, the output current is gradually increased again atthe reduced frequency level until the stimulation results in anintolerable side effect level or the target output current (e.g., 2.5mA) is reached. At decision step 1006, if the target output current hasnot been reached but the maximum tolerable side effects have beenexceeded, the process proceeds to step 1007.

In step 1007, the titration session is concluded. The stimulation systemmay be programmed to continue delivering the stimulation signal at thelast parameter settings achieved prior to conclusion of the titrationsession. After a period of time, another titration session may beinitiated and the process returns to step 1001. This can be any periodof time sufficient to permit the patient to adjust to the increasedstimulation levels. This can be, for example, as little as approximatelytwo or three days, approximately one to two weeks, approximately four toeight weeks, or any other desired period of time.

In some embodiments, the titration sessions are automatically initiatedby the stimulation system or initiated by the patient without requiringany intervention by the health care provider. This can eliminate theneed for the patient to schedule a subsequent visit to the health careprovider, thereby potentially reducing the total amount of time neededfor the titration process to complete. In these embodiments, thestimulation system may include a physiological monitor, e.g., animplanted heart rate sensor, that communicates with the stimulationsystem's control system to enable the control system to detect thepatient's physiological response to the titration and automatically makeadjustments to the titration processes described herein with reduced orno inputs from the patient or health care provider. The monitoredsignals can also enable the control system to detect when the targetphysiological response has been achieved and conclude the titrationprocess. The stimulation system could in addition or alternativelyinclude a patient control input to permit the patient to communicate tothe control system that the acceptable side effect level has beenexceeded. This control input may comprise an external control magnetthat the patient can swipe over the implanted neurostimulator, or otherinternal or external communication device that the patient can use toprovide an input to the control system. In these automatically initiatedtitration sessions, the stimulation system may be configured to wait aperiod of time after completing one session before initiating the nextsession. This period of time may be predetermined, e.g., two or threedays, or programmable.

Returning to decision step 1006, if the target output current has notbeen reached but the maximum tolerable side effects have been exceeded,the process proceeds to step 1008. In step 1008, the output current isreduced one increment to restore an acceptable side effect condition,and the frequency is gradually increased until the stimulation resultsin an intolerable side effect level or the target frequency (e.g., 10Hz) is reached. At decision step 1009, if the target frequency has notbeen reached but the maximum tolerable side effects have been exceeded,the frequency is reduced to restore an acceptable side effect level andthe process proceeds to step 1007. Again, in step 1007, the currenttitration session is concluded and the stimulation system may beprogrammed to continue delivering the stimulation signal at the lastparameter settings achieved prior to conclusion of the titrationsession.

At decision step 1009, if the target frequency has been reached beforethe maximum tolerable side effects have been exceeded, the duty cycle isgradually increased until the stimulation results in an intolerable sideeffect level or the target duty cycle (e.g., 14 sec ON and 1.1 min OFF)is reached, at which point the process proceeds to step 1007 and thetitration session is concluded and ongoing stimulation delivered at thelast intensity eliciting acceptable side effect levels.

Returning to decision step 1003, if the target output current has beenachieved before the maximum tolerable side effects are exceeded, theprocess proceeds to step 1011. In step 1011, the pulse width isgradually increased until the stimulation results in an intolerable sideeffect level or the target pulse width (e.g., 250 μsec) is reached. Insome embodiments, before step 1011, the output current is reduced (e.g.,by up to 50%), and the pulse width may be increased in step 1011 at thatreduced output current. After the target pulse width is achieved, theoutput current may be restored to the target output current. In otherembodiments, the output current may be reduced (or may be retained atthe reduced level established prior to step 1011, as described above),and the frequency and duty cycle are gradually increased in step 1013 atthat reduced output current. This reduction in output current afterachieving the target output current may enable the patient to maintaintolerability with increasing pulse width, frequency, and duty cycle insubsequent titration steps.

At decision step 1012, if the target pulse width has not been achievedbefore the maximum tolerable side effects have been exceeded, the pulsewidth is reduced to restore an acceptable side effect level and theprocess proceeds to step 1007. Again, in step 1007, the currenttitration session is concluded.

If at decision step 1012, the target pulse width has been achievedbefore the maximum tolerable side effects have been exceeded, theprocess proceeds to step 1013. In step 1013, the frequency and dutycycle are increased until the stimulation results in an intolerable sideeffect level or the target frequency and target duty cycle are reached.The frequency and duty cycle can be increased in step 1012simultaneously, sequentially, or on an alternating basis.

At decision step 1014, if the target frequency and target duty cyclehave not been achieved before the maximum tolerable side effects havebeen exceeded, the pulse width and/or frequency are reduced to restorean acceptable side effect level and the process continues to step 1007and the titration session is concluded.

At decision step 1014, if the target pulse width and target frequencyhave been achieved before the maximum tolerable side effects have beenexceeded, all of the stimulation parameters will have reached theirtarget levels and the titration process concludes at step 1015. Thestimulation therapy may proceed with the maintenance dose at the targetstimulation levels.

In some embodiments, in step 1004, instead of reducing the frequency inorder to facilitate increase of the output current, the pulse width maybe reduced. For example, embodiments where the target pulse width is 250μsec, the pulse width may be reduced, e.g., to 150 μsec or less. Then,the method proceeds to step 1005, in which the output current isgradually increased again at the reduced pulse width level until thestimulation results in an intolerable side effect level or the targetoutput current (e.g., 2.5 mA) is reached.

Therapy can also be autonomously titrated by the neurostimulator 12 inwhich titration progressively occurs in a self-paced, self-monitoredfashion. The progression of titration sessions may occur on anautonomous schedule or may be initiated upon receipt of an input fromthe patient. Ordinarily, the patient 10 is expected to visit hishealthcare provider to have the stimulation parameters stored by theneurostimulator 12 in the recordable memory 29 reprogrammed using anexternal programmer. Alternatively, the neurostimulator 12 can beprogrammed to automatically titrate therapy by up titrating the VNSthrough periodic incremental increases using titration sessions asdescribed above. The titration process 1000 will continue until theultimate therapeutic goal is reached.

Following the titration period, therapeutic VNS, as parametricallydefined by the maintenance dose operating mode, is delivered to at leastone of the vagus nerves. The stimulation system 11 delivers electricaltherapeutic stimulation to the cervical vagus nerve of a patient 10 in amanner that results in creation and propagation (in both afferent andefferent directions) of action potentials within neuronal fibers ofeither the left or right vagus nerve independent of cardiac cycle.

In a further embodiment, the sensed heart rate data can be used toanalyze therapeutic efficacy and patient condition. For instance,statistics could be determined from the sensed heart rate, eitheronboard by the neurostimulator 12 or by an external device, such as aprogramming computer following telemetric data retrieval. The sensedheart rate data statistics can include determining a minimum heart rateover a stated time period, a maximum heart rate over a stated timeperiod, an average heart rate over a stated time period, and avariability of heart rate over a stated period, where the stated periodcould be a minute, hour, day, week, month, or other selected timeinterval. Still other uses of the heart rate sensor 31 and the sensedheart rate data are possible.

FIG. 11A is a simplified block diagram of an implanted neurostimulationsystem 1100 in accordance with embodiments of the present invention. Theimplanted neurostimulation system 1100 comprises a control system 1102comprising a processor programmed to operate the system 1100, a memory1103, an optional physiological sensor 1104, and a stimulation subsystem1106. The physiological sensor 1104 may be configured to monitor any ofa variety of patient physiological signals and the stimulation subsystem1106 may be configured to deliver a stimulation signal to the patient.In one example, the physiological sensor 1104 comprises an ECG sensorfor monitoring heart rate and the stimulation subsystem 1106 comprises aneurostimulator 12 programmed to deliver ON-OFF cycles of stimulation tothe patient's vagus nerve.

The control system 1102 is programmed to activate the neurostimulator 12to deliver varying stimulation intensities to the patient and to monitorthe physiological signals in response to those stimulation signals.

The external programmer 1107 shown in FIG. 11A may be utilized by aclinician or by the patient for communicating with the implanted system1100 to adjust parameters, activate therapy, retrieve data collected bythe system 1100 or provide other input to the system 1100. In someembodiments, the external programmer 1107 may be configured to programthe implanted system 1100 with a prescribed time or window of timeduring which titration sessions may be initiated. This can be used toprevent a titration session from occurring at night when the patient'ssleep is likely to be disturbed by the increase in stimulation intensityand resulting side effects.

Patient inputs to the implanted system 1100 may be provided in a varietyof ways. The implanted system 1100 may include a patient input sensor1105. As described above, a patient magnet 1130 may be used to provideexternal input to the system 1100. When the patient magnet 1130 isplaced on the patient's chest in close proximity to the implanted system1100, the patient input sensor 1105 will detect the presence of themagnetic field generated by the patient magnet 1130 and provide acontrol input to the control system 1102. The system 1100 may beprogrammed to receive patient inputs to set the time of day during whichtitration sessions are to be initiated.

In other embodiments, the patient input sensor 1105 may comprise amotion sensor, such as an accelerometer, which is configured to detecttapping on the surface of the patient's chest. The patient may usefinger taps in one or more predetermined patterns to provide controlinputs to the implanted system 1100. For example, when the motion sensordetects three rapid taps to the patient's chest, that may trigger anoperation on the implanted system 1100 (e.g., to initiate a titrationsession). Alternatively, if the motion sensor detects a predeterminedpattern of taps during a titration session, the implanted system 1100will interpret those taps as a patient input indicating that thepatient's tolerance zone boundary has been exceeded.

In other embodiments, the patient input sensor 1105 may comprise anacoustic transducer or other sensor configured to detect acousticsignals. The system 1100 may be programmed to interpret the detection ofcertain sounds as patient inputs. For example, the patient may utilizean electronic device, such as a smartphone or other portable audiodevice, to generate one or more predetermined sequences of tones. Thesystem 1100 may be programmed to interpret each of these sequences oftones as a different patient input.

In other embodiments, the patient input sensor 1105 may be configured todetect when a patient is coughing, which can be interpreted by thesystem 1100 as an indication that the increased stimulation intensityexceeds the patient's tolerance zone boundary. The coughing could bedetected by an accelerometer to detect movement of the patient's chest,an acoustic transducer to detect the sound of the patient's coughing, orboth.

The titration of the stimulation signal delivery and the monitoring ofthe patient's physiological response (e.g., heart rate) may beadvantageously implemented using control system in communication withboth the stimulation subsystem 1106 and the physiological sensor 1104,such as by incorporating all of these components into a singleimplantable device. In accordance with other embodiments, the controlsystem may be implemented in a separate implanted device or in anexternal programmer 1120 or other external device, as shown in FIG. 11B.The external programmer 1120 in FIG. 11B may be utilized by a clinicianor by the patient for adjusting stimulation parameters. The externalprogrammer 1120 is in wireless communication with the implanted medicaldevice 1110, which includes the stimulation subsystem 1116. In theillustrated embodiment, the physiological sensor 1114 is incorporatedinto the implanted medical device 1110, but in other embodiments, thesensor 1114 may be incorporated into a separate implanted device, may beprovided externally and in communication with the external programmer1120, or may be provided as part of the external programmer 1120.

FIGS. 13-17 are flow diagrams illustrating a more detailedmulti-threaded titration process 1300 that can be implemented with astimulation system in accordance with embodiments of the presentinvention. Similar to titration process 1000 described above, thetitration process 1300 begins at step 1301, in which the titrationprocess is initiated and the stimulation system delivers stimulation tothe patient. If this is the first titration session, then thestimulation would be delivered with an initial stimulation parameterset. If this is a subsequent titration session, then the stimulationintensity would remain at the same level at the conclusion of theprevious titration session. In step 1302, an Intolerance DetectionThread 1400 (shown in FIG. 14) is initiated, and in step 1303, aTitration Execution Thread 1500 (shown in FIG. 15) is initiated. Inprocess 1300, the two threads, 1400 and 1500, execute concurrentlyduring the titration session. The process 1300 continues until thetitration session is deemed complete in step 1304, as will be describedin greater detail below. In step 1305, the Intolerance Detection Thread1400 is terminated and in step 1306, the titration process isterminated.

FIG. 14 is a flowchart illustrating an Intolerance Detection Thread1400, which is a process for continuously monitoring the patient todetect stimulation intolerance in the patient. The Intolerance DetectionThread 1400 begins at step 1401, and in decision step 1402, thestimulation system continuously monitors for an indication that a sideeffect intolerance level has been reached. Any of the various methodsfor detecting intolerance described herein may be utilized for thismonitoring. As long as intolerance is not detected in decision step1402, the Intolerance Detection Thread 1400 continues monitoring forintolerance. If intolerance is detected in decision step 1402, then thatintolerance is communicated in step 1403 to the subroutine currentlybeing executed, as will be described in greater detail below.

FIG. 15 is a flowchart illustrating a Titration Execution Thread 1500,which is a process for adjusting stimulation parameters during atitration session. The Titration Execution Thread 1500 begins at step1501, decision step 1502 determines whether the stimulation amplitude isat the target level or the amplitude titration subroutine has beendetermined to have failed. In the initial titration session, theamplitude will be set at the initial level, which is lower than thetarget level, and the amplitude titration subroutine will not yet havebeen initiated, and will therefore not yet be determined to have failed.Accordingly, the thread 1500 will proceed to the Amplitude Subroutine1600 (shown in FIG. 16).

If the response to either query in decision step 1502 is true, then theprocess 1500 will proceed to decision step 1503. In decision step 1503,if the amplitude titration subroutine has been deemed to have failed,then the process 1500 proceeds to step 1505, in which the titrationsession is deemed completed and the Titration Execution Thread 1500 willbe terminated. If the amplitude titration subroutine has not been deemedto have failed, then the process 1500 proceeds to decision step 1504. Indecision step 1504, the stimulation system determines whether the pulsewidth (PW) is at the target level or the pulse width titrationsubroutine has been determined to have failed. If the response to eitherquery in decision step 1504 is true, then the process 1500 proceeds tostep 1505, in which the titration session is deemed completed and theTitration Execution Thread 1500 will be terminated. If both queries indecision step 1504 are false, then the process 1500 proceeds to thePulse Width Subroutine 1700 (shown in FIG. 17).

FIG. 16 is a flowchart illustrating an Amplitude Subroutine 1600, whichis a more detailed process for adjusting stimulation parameters during atitration process in which an acclimation interval timeout may beincreased if stimulation amplitude increases are not tolerated by thepatient. The Amplitude Subroutine begins at step 1601 a, in which thestimulation amplitude is incrementally increased. Next, in step 1601 b,an acclimation interval timer is reset to zero. The stimulationamplitude may be increased in any desired increment. In someembodiments, the increase is predetermined and incremented by the sameamount with each increase. In other embodiments, the increases may bevariable, as a function of any desired input. In some cases, thepatient's responses to past increments may be used to modify theincremental increase. For example, if the patient has not experiencedundesirable side effects with past increases, subsequent increases maybe incremented by a larger amount. In yet other embodiments, theincrements may be a function of the absolute amplitude. For example, theincrements may increase in size after the amplitude has been increasedbeyond a certain threshold (e.g., 2.0 mA). In another example, theincrements may be a percentage (e.g., 5%, 10%, or 20%) of the currentstimulation amplitude. In both examples, the increments may increase asthe current amplitude increases, since the patient may have a greatertolerance for amplitude increases at that point of the titrationprocess.

The process proceeds to decision step 1602, which determines whether theacclimation interval timer indicates that an acclimation intervaltimeout has been reached. The acclimation interval timeout is the timeinterval between stimulation increases. During this acclimation intervalthe patient's brain becomes less sensitive to the vagus stimulationincrease. The acclimation interval timeout can be a predetermined lengthof time, or may be variable within a titration session, as describedbelow with respect to step 1607. The initial acclimation intervaltimeout could be, for example, about 2-3 days for an aggressivetitration schedule, or 7-14 days for a conservative titration schedule.

If the acclimation interval timeout has not been reached (which would bethe case during the initial traversal through the Amplitude Subroutine1600), then the subroutine proceeds from decision step 1602 to decisionstep 1605, in which the communication regarding intolerance in step 1403of the Intolerance Detection Thread 1400 is consulted and if intoleranceis not detected, then the subroutine 1600 returns to step 1602, in whichit is again determined whether the acclimation interval timeout has beenreached. As a result, as long as the patient does not experienceintolerable side effects, the system will maintain stimulation at theincreased amplitude initiated in step 1601 a. This ensures that thepatient is provided with the full acclimation interval before thestimulation amplitude is again increased. If the acclimation intervaltimer indicates that the acclimation interval timeout has been reached,then the subroutine proceeds to step 1603, in which the amplitudetitration subroutine will be deemed to have not failed (e.g., theAmplitude Titration Failure variable is set to FALSE), and in step 1604,the process returns to decision step 1502 in FIG. 15. This representsthe success path for the titration in which the patient has toleratedthe increase in stimulation amplitude. Returning to FIG. 15, the processwill return to step 1502, in which the system again determines whetherthe stimulation amplitude is at the target level or the amplitudetitration subroutine has been determined to have failed. If neither istrue, then the process returns to the Amplitude Subroutine 1600, thestimulation amplitude is incrementally increased in step 1601 a, theacclimation interval timer is reset in step 1601 b, and the patient isagain provided with a period of time to acclimate to the newly increasedstimulation amplitude.

In the embodiment illustrated in FIG. 16, the acclimation interval isvariable depending on the patient's response to changes in stimulationamplitude, and if an increase in amplitude in step 1601 a is intolerableto the patient, the amplitude may be decreased and the patient isprovided with an extended acclimation interval timeout at that decreasedamplitude to provide the patient with an increased amount of time toacclimate to the stimulation. In this embodiment, it may be desirable tohave a predetermined maximum acclimation interval, such that once theacclimation interval timeout has been increased to a level where itequals or exceeds the maximum acclimation interval, the titrationprocess will then attempt to adjust a different stimulation parameterinstead of amplitude. The maximum acclimation interval may be any periodof time desired. In some embodiments, the maximum acclimation intervalcan be set at a multiple of the initial acclimation interval timeout,e.g., 2-5 times the initial acclimation interval timeout.

In step 1605, if the Intolerance Detection Thread 1400 has communicatedthat a side effect intolerance level has been reached, then theAmplitude Subroutine 1600 proceeds to decision step 1606. In decisionstep 1606, if the acclimation interval timeout is still less than themaximum acclimation interval, then the subroutine 1600 proceeds to step1607. In step 1607, the amplitude is decreased by the preset incrementand the acclimation interval timeout is increased by some amount, andthe subroutine 1600 returns to step 1601 b, in which the acclimationinterval timer is reset to zero and stimulation is delivered at thereduced amplitude. The acclimation interval timeout may be increased byany amount, such as, for example, a predetermined period of time (e.g.,1-3 days), or by a multiple of the initial acclimation interval timeout(e.g., double the initial acclimation interval timeout).

In step 1605, if the Intolerance Detection Thread 1400 has notcommunicated that a side effect intolerance level has been reached, thenthe process will return to 1602, where subroutine will repeat in a loopand continue delivering stimulation at that amplitude until theacclimation interval timeout has been reached in step 1602 orintolerance detected in step 1605.

In decision step 1606, if the acclimation interval timeout has beenincreased in step 1607 to the point where it has reached the maximumacclimation interval, then the subroutine 1600 proceeds to decision step1608, in which the system will attempt to bring the patient to thetarget amplitude by reducing the stimulation frequency. The stimulationsystem can include a predetermined list of fallback frequencies toattempt when the target amplitude cannot be tolerably achieved in atitration session. This list depends upon the starting frequency and thedesired granularity for making downward adjustments. The list can be,for example, 20 Hz, 15 Hz, 10 Hz, 5 Hz, 2 Hz, and 1 Hz. If in decisionstep 1608 it is determined that all of the frequencies in the list offallback frequencies have not yet been attempted during this titrationsession, then the subroutine 1600 proceeds to step 1609, in which thenext frequency in the list is selected and stimulation applied at thatnew frequency. The subroutine 1600 then returns to 1601 b, in which theacclimation interval timer is reset to zero and stimulation delivered tothe patient at that new frequency. If in decision step 1608 it isdetermined that all of the frequencies in the list of fallbackfrequencies have already been attempted during this titration session,then it is concluded that the patient was not able to tolerate thestimulation even after attempting all of the reduced frequencies in thefallback frequency list, and the subroutine 1600 proceeds to decisionstep 1610.

In decision step 1610, if it is determined that the current stimulationOFF time is greater than a predetermined minimum OFF time, then thesubroutine 1600 proceeds to step 1611, in which the stimulation OFF timeis decreased by a predetermined increment. The minimum OFF time couldbe, for example, 10, 20, 30 seconds, or longer. The subroutine 1600 thenreturns to step 1601 b, in which the acclimation interval timer is resetto zero and stimulation delivered to the patient with the decreased OFFtime.

In decision step 1610, if it is determined that the current stimulationOFF time is not greater than the predetermined minimum OFF time, thenthe subroutine 1600 proceeds to step 1612, in which all of thestimulation parameters are restored to the last set of stimulationparameters that did not result in patient intolerance. In step 1613, theamplitude titration subroutine will be deemed to have failed (e.g., theAmplitude Titration Failure variable is set to TRUE), and in step 1614,the process returns to decision step 1502 in FIG. 15. Because theamplitude titration subroutine will be deemed to have failed, theprocess will proceed from decision step 1502 to decision step 1503, andthen to step 1505.

After one or more titration sessions in which the Amplitude Subroutine1600 has been performed, the target stimulation amplitude shouldeventually be achieved. At this point, the thread 1500 will proceedthrough decision steps 1502 and 1503 to decision step 1504, in which thesystem determines whether the stimulation pulse width is at the targetlevel or the pulse width titration subroutine has been determined tohave failed. The first time the Titration Execution Thread 1500 isexecuted, the pulse width will be set at a predetermined initial level,which is lower than the target PW level, and the PW titration subroutinewill not yet have been initiated, and will therefore not yet bedetermined to have failed. Accordingly, the thread 1500 will proceed tothe PW Subroutine 1700 (shown in FIG. 17).

FIG. 17 is a flowchart illustrating a Pulse Width (PW) Subroutine 1700,which is similar to the Amplitude Subroutine 1600, but utilizing changesin the stimulation pulse width instead of the amplitude. The PWSubroutine begins at step 1701 a, in which the stimulation pulse widthis incrementally increased. Next, in step 1701 b, an acclimationinterval timer is reset to zero. As with the increases in amplitude instep 1601 b, the stimulation pulse width may be increased in any desiredincrement. The process proceeds to decision step 1702, similar todecision step 1602, which determines whether the acclimation intervaltimer indicates that an acclimation interval timeout has been reached.If the acclimation interval timeout has been reached, then thesubroutine proceeds to step 1703, in which the PW titration subroutinewill be deemed to have not failed (e.g., the PW Titration Failurevariable is set to FALSE), and in step 1704, the process returns todecision step 1504 in FIG. 15. This represents the success path for thetitration in which the patient has tolerated the increase in stimulationpulse width.

If the acclimation interval timeout has not been reached, then thesubroutine proceeds from step 1702 to decision step 1705, in which thecommunication regarding intolerance in step 1403 of the IntoleranceDetection Thread 1400 is consulted and if intolerance is not detected,then the subroutine 1700 returns to step 1702, in which it is againdetermined whether the acclimation interval timeout has been reached. Asa result, as long as the patient does not experience intolerable sideeffects, the system will maintain stimulation at the increased pulsewidth initiated in step 1701 a. This ensures that the patient isprovided with the full acclimation interval before the stimulation pulsewidth is again increased. If the acclimation interval timer indicatesthat the acclimation interval timeout has been reached, then thesubroutine proceeds to step 1703, in which the pulse width titrationsubroutine will be deemed to have not failed (e.g., the PW TitrationFailure variable is set to FALSE), and in step 1704, the process returnsto decision step 1504 in FIG. 15. This represents the success path forthe titration in which the patient has tolerated the increase instimulation pulse width. Returning to FIG. 15, the process will returnto step 1504, in which the system again determines whether thestimulation pulse width is at the target level or the pulse widthtitration subroutine has been determined to have failed. If neither istrue, then the process returns to the PW Subroutine 1700, thestimulation pulse width is incrementally increased in step 1701 a, theacclimation interval timer is reset in step 1701 b, and the patient isagain provided with a period of time to acclimate to the newly increasedstimulation pulse width.

If in step 1705, the Intolerance Detection Thread 1400 has communicatedthat a side effect intolerance level has been reached, then the PWSubroutine 1700 proceeds from decision step 1705 to decision step 1706.In decision step 1706, if the acclimation interval timeout is still lessthan the maximum acclimation interval, then the subroutine 1700 proceedsto step 1707. In step 1707, the pulse width is decreased by the presetincrement and the acclimation interval timeout is increased by someamount, and the subroutine 1700 returns to step 1701 b, in which theacclimation interval timer is reset to zero and stimulation is deliveredat the reduced pulse width.

In step 1705, if the Intolerance Detection Thread 1400 has notcommunicated that a side effect intolerance level has been reached, thenthe process will return to 1702, where subroutine will repeat in a loopand continue delivering stimulation at that pulse width until theacclimation interval timeout has been reached in step 1702 orintolerance detected in step 1705.

In decision step 1706, if the acclimation interval timeout has beenincreased in step 1707 to the point where it has reached the maximumacclimation interval, then the subroutine 1700 proceeds to decision step1708, in which the system will attempt to bring the patient to thetarget pulse width by reducing the stimulation frequency. As withsubroutine 1600, the stimulation system can include a predetermined listof fallback frequencies to attempt when the target pulse width cannot betolerably achieved in a titration session. If in decision step 1708 itis determined that all of the frequencies in the list of fallbackfrequencies have not yet been attempted during this titration session,then the subroutine 1700 proceeds to step 1709, in which the nextfrequency in the list is selected and stimulation applied at that newfrequency. The subroutine 1700 then returns to 1701 b, in which theacclimation interval timer is reset to zero and stimulation delivered tothe patient at that new frequency. If in decision step 1708 it isdetermined that all of the frequencies in the list of fallbackfrequencies have already been attempted during this titration session,then it is concluded that the patient was not able to tolerate thestimulation even after attempting all of the reduced frequencies in thefallback frequency list, and the subroutine 1700 proceeds to decisionstep 1710.

In decision step 1710, if it is determined that the current stimulationOFF time is greater than a predetermined minimum OFF time, then thesubroutine 1700 proceeds to step 1711, in which the stimulation OFF timeis decreased by a predetermined increment. The predetermined minimum OFFtime for the PW subroutine 1700 could be the same or different than thepredetermined minimum OFF time for the amplitude subroutine 1600. Thealgorithm may be customizable with any desired OFF time for either theamplitude subroutine 1600 and PW subroutine 1700, depending on patientneeds the desire to customize the titration for individual patients. Thesubroutine 1700 then returns to step 1701 b, in which the acclimationinterval timer is reset to zero and stimulation delivered to the patientwith the decreased OFF time.

In decision step 1710, if it is determined that the current stimulationOFF time is not greater than the predetermined minimum OFF time, thenthe subroutine 1700 proceeds to step 1712, in which all of thestimulation parameters are restored to the last set of stimulationparameters that did not result in patient intolerance. In step 1713, thePW Subroutine will be deemed to have failed (e.g., the AmplitudeTitration Failure variable is set to TRUE), and in step 1714, theprocess returns to decision step 1504 in FIG. 15. Because the amplitudetitration subroutine will be deemed to have failed, the process willproceed from decision step 1504 to step 1505, at which point thetitration session will be deemed complete and the titration executionthread 1500 terminated.

Returning to the process 1300 in FIG. 13, the titration will bedetermined to be complete in decision step 1304, and the process 1300will continue to step 1305, at which the intolerance detection thread1400 will be terminated. Finally, the process 1300 will proceed to step1306, at which point the titration session is terminated.

Personalized Titration Via Adaptive Parametric Modification

Titration is a method of varying over time stimulation parametersemployed by an implanted device to deliver stimulation current, untiltherapeutic levels become tolerated by the patient. Embodiments providedabove describe automated titration processes used to gradually increasethe stimulation intensity to a desired therapeutic level. Duringperiodic titration sessions, the stimulation intensity is increaseduntil the maximum tolerable side effects are exceeded, at which pointthe stimulation intensity is reduced to a tolerable level and thepatient is provided with a period of time to adapt to the new intensitylevels before the next titration session is initiated. In someembodiments, the titration sessions may occur on a regular schedule(e.g., every two weeks), with an acclimation interval in between eachtitration session during which time stimulation at a tolerable intensitylevel is delivered. Then, at each titration session, the variousstimulation parameters are increased by predetermined increments.However, patients adapt to increased stimulation intensity levelsdifferently and utilizing the same acclimation intervals and otherstimulation parameter incremental changes for all patients may notprovide optimal results for every patient.

For example, patients adapt to increased stimulation intensity levels atdifferent rates, so the minimum acclimation interval required before thenext titration session can successfully be initiated varies. In otherembodiments, parameters other than or in addition to the acclimationinterval may be adjusted based on the actual adaption experienced by thepatient. The parameters that might be adjusted include, for example:current amplitude, pulse width, frequency, and OFF time.

In accordance with some embodiments of the present invention, anautomated titration process is provided which utilizes an acclimationinterval between titration sessions that may be adjusted based on thepatient's response to the stimulation. FIG. 12 illustrates a titrationprocess 1200 with a variable acclimation interval. Steps 1201-1203 aresimilar to steps 901-903 illustrated in FIG. 9 and described above.However, in step 1204, an outcome measure for the titration sessions isanalyzed. In step 1205, the acclimation interval between subsequenttitration sessions is adjusted based on the analyzed outcome measure. Ifthe outcome measure indicates that the patient is adapting to thestimulation at a slower than expected rate, then the acclimationinterval may be increased to provide the patient with additional time torecover and adapt to each set of increased stimulation intensities.Conversely, if the outcome measure indicates that the patient isadapting to the stimulation at a faster than expected rate, then theacclimation interval may be decreased to accelerate the adaption processand reduce the overall time required to complete the titration processand achieve a tolerable therapeutic maintenance dose level.Alternatively or in addition, the increments for increases in one ormore stimulation parameters (e.g., current amplitude, pulse width,frequency, and OFF time) can be increased so that each titration stepraises the stimulation parameter(s) by larger amounts.

Any of a variety of outcome measures may be used. In some embodiments,the outcome measure is the patient's tolerance of a targeted increase inone or more of the stimulation parameters. For example, if the patientis unable to tolerate any increase in stimulation output current (orstimulation parameter) over the course of two or more titration sessionsseparated by a default acclimation interval (e.g., two weeks), it may beconcluded that the patient is adapting to the stimulation at a slowerthan expected rate. In response, the acclimation interval betweensubsequent titration sessions may be increased (to, e.g., three or moreweeks). If the patient continues to be incapable of tolerating anyincrease in stimulation output current in subsequent titration sessions,then the acclimation interval may be increased again (to, e.g., four ormore weeks).

In some cases, the patient may initially adapt to the increasedstimulation intensity at a slower than expected rate, but after theacclimation interval is increased and subsequent titration sessions aresuccessful at achieving the desired outcome measure, the patient'sadaptation may accelerate, thereby permitting reduction of theacclimation interval back to the initial interval length. Accordingly,if the patient begins to adapt to the titration sessions after anincrease in the acclimation interval, the system 1100 may be programmedto gradually reduce the acclimation interval in subsequent titrationsessions.

In various embodiments described above, after a titration session isterminated, the system may be programmed to continue deliveringstimulation at the last parameter settings achieved prior to conclusionof the titration session at an intensity just below the patient'stolerance zone boundary. This stimulation is delivered at this constantintensity until the next titration session is initiated. In some cases,patients are capable of enduring stimulation intensities just past thetolerance zone boundary for limited periods of time. The intensitylevels just past the tolerance zone boundary may be considered by thepatient as “moderately tolerable.” Patients may be willing to endurestimulation at the moderately tolerable levels for limited periods oftime if it results in acceleration of the adaption process.

In accordance with some embodiments, after a titration session isconcluded or at any desired periodicity during the acclimation interval,an elevated stimulation session may be initiated, during which timestimulation at moderately tolerable levels exceeding the tolerance zoneboundary is delivered. This elevated stimulation session may continuefor any desired period of time, such as, e.g., several minutes orseveral hours, after which point the stimulation intensity will bereduced to a sustained stimulation intensity level below the tolerancezone boundary. In some embodiments, the elevated stimulation session maycontinue for less than one day, while the sustained stimulation isdelivered for a period greater than one day, or the elevated stimulationsession may continue for less than six hours, while the sustainedstimulation is delivered for a period greater than one week. Any desiredperiods of time may be used.

Interactive Training Sessions

Various methods are described herein for titrating stimulation bygradually increasing stimulation intensity until the patient's tolerancezone boundary is reached or exceeded. In accordance with embodiments ofthe present invention, systems and methods are provided for performinginteractive training sessions in clinic for patients about to undergotitration on an ambulatory basis. The methods permit clinicians tocreate a series of stimulation intensities (ranging from un-noticeableto noticeable but tolerable to intolerable), the patient's response toeach stimulation, and the implanted device's response to patient inputs.

The implanted medical device 1100 may be used in conjunction with anexternal clinician programmer 1107 and patient input device (e.g.,patient magnet 1130 or wireless-communications-enabled patient controldevice), to perform the titration processes on an ambulatory basis asdescribed above, but is also programmed to execute in a training mode.This training mode may be initiated by the clinician using the clinicianprogrammer 1107 while the patient is physically in the clinic fortreatment and training. The training mode may be similar to thetitration sessions described above, except that the increasingstimulation is initiated by the clinician using the programmer 1107 orautomatically on an accelerated schedule. When the stimulation intensityreaches the patient's tolerance zone boundary, the patient can use anyof the herein described methods for providing a patient input to thedevice 1100 to indicate that the tolerance zone boundary has beenreached. When in training mode, the device 1100 may also transmit to theclinician programmer 1107 information regarding the stimulation beingdelivered. The programmer 1107 may include a display which permits theclinician to observe the increasing intensity and receive a report ofthe intensity level that elicited the patient input indicating that thetolerance zone boundary was reached. The display on the programmer 1107may also be used to display feedback or instructions to the patient.

The clinician may run the training mode multiple times so that thepatient may become proficient at recognizing stimulation levels that arenoticeable but tolerable, and distinguishing those tolerable levels fromthe truly intolerable stimulation levels. This can also provide trainingfor the patient in the proper use of the patient input device. In someembodiments, the programmer 1107 may be used to select the stimulationparameter to be increased (e.g., output current, frequency, pulse width,or duty cycle), so that the patient and clinician can observe thedifferent responses that may be elicited depending on the parameterbeing adjusted. In some embodiments, the programmer 1107 may beconfigured to pause the titration algorithm to hold the stimulation at asingle level. This may be useful for facilitating a tolerance zoneassessment by providing the patient additional time to experience thestimulation. The programmer 1107 may also be used to terminate thetraining mode and return the device 1100 to its normal ambulatory mode,during which the desired ambulatory titration process may be performed.

The training mode may also comprise an algorithm that sequencesstimulation changes based on the training mode parameters programmed bythe clinician. Stimulation may be altered on a highly accelerated timescale in order to move the patient from tolerable tonoticeable-but-tolerable to intolerable stimulation levels within thenormal office follow-up period. This accelerated time scale may be, forexample, five, ten or fifteen minutes for all training. This is incontrast to the ambulatory mode titration process that seeks to advancetherapy levels without the patient exceeding the tolerance-zoneboundary. Having the patient experience all three tolerance phases in asingle clinic visit can provide valuable patient training, resulting inaccelerated adaptation speed.

The system 1100 may be programmed with an autonomous monitor to ensurethat the training mode terminates automatically after a certain periodhas elapsed, even in the absence of a termination input from theclinician programmer. For example, the system 1100 may be programmed toautomatically time-out and terminate the training mode 24 hours afterinitiation. After this automatic time-out, the system 1100 mayautomatically initiate the ambulatory mode.

As a result, the system may enable patients to experience stimulationlevels (usually following a stimulation increase) that may beunacceptable. Patients may also learn how to effectively deal with theintolerance through the use of the external patient input device.Clinicians can learn how individual patients react to variousstimulation levels and the patients' cognitive ability to deal withunacceptable stimulation autonomously. Clinicians may also gain a senseof stimulation increases that an individual patient can tolerate andadjust the ambulatory titration algorithm accordingly.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope. Forexample, in various embodiments described above, the stimulation isapplied to the vagus nerve. Alternatively, spinal cord stimulation (SCS)may be used in place of or in addition to vagus nerve stimulation forthe above-described therapies. SCS may utilize stimulating electrodesimplanted in the epidural space, an electrical pulse generator implantedin the lower abdominal area or gluteal region, and conducting wirescoupling the stimulating electrodes to the generator.

What is claimed is:
 1. A method of operating an implantable medicaldevice (IMD) comprising a neurostimulator coupled to an electrodeassembly, said method comprising: initiating a plurality of titrationsessions, each titration session separated from an adjacent titrationsession by an acclimation interval, wherein the titration sessionscomprise activating the IMD to deliver a stimulation signal of graduallyincreasing intensity until the patient exceeds a side effect tolerancezone boundary; analyzing an outcome measure of the plurality oftitration sessions; and modifying one or more stimulation parametersbased on the analyzed outcome measure.
 2. The method according to claim1, wherein: the modifying one or more stimulation parameters comprisesmodifying an increment for gradually increasing one or more stimulationparameters in order to increase stimulation intensity during asubsequent titration session.
 3. The method according to claim 1,wherein: the modifying the increment comprises modifying the incrementfor gradually increasing one or more of the following: currentamplitude, pulse width, frequency, and OFF time.
 4. The method accordingto claim 1, wherein: the modifying one or more stimulation parameterscomprises modifying the acclimation interval until a subsequenttitration session based on the analyzed outcome measure.
 5. The methodaccording to claim 4, wherein: said modifying the accommodation periodcomprises increasing the acclimation interval in response to an outcomemeasure indicating slower than expected patient adaptation.
 6. Themethod according to claim 4, wherein: the outcome measure comprises atarget increase in stimulation intensity; and said modifying theacclimation interval comprises increasing the acclimation interval inresponse to a failure to achieve the target increase in stimulationintensity.
 7. The method according to claim 4, wherein: the stimulationsignal comprises an output current, a frequency, a pulse width, and aduty cycle; the outcome measure comprises a target increase in outputcurrent; and said modifying the acclimation interval comprisesincreasing the acclimation interval in response to a failure to achievethe target increase in output current over the plurality of titrationsessions.
 8. The method according to claim 4, wherein: said modifyingthe accommodation period comprises decreasing the accommodation periodbefore the subsequent titration session in response to an outcomemeasure indicating faster than expected patient adaptation.
 9. Themethod according to claim 4, further comprising: during the acclimationintervals, activating the IMD to deliver a stimulation signal at anintensity resulting in an acceptable side effect level.
 10. The methodaccording to claim 1, further comprising: determining a maintenancedosage level corresponding to a tolerable stimulation intensityachieving adequate adaptation; and delivering stimulation at themaintenance dosage level.
 11. A method according to claim 10, whereinadequate adaptation comprises one or more of: an acceptable side effectlevel, a target physiological response, and a target stimulationparameter set.
 12. The method according to claim 1, further comprising:receiving a patient input indicating the side effect tolerance zoneboundary.
 13. The method according to claim 12, wherein: said receivingthe patient input comprises receiving a radio frequency (RF) signal froman external communications device, said wireless signal indicating thatthe patient has reached the side effect tolerance zone boundary.
 14. Themethod according to claim 12, wherein: said receiving the patient inputcomprises detecting a magnetic field indicating that the patient hasreached the side effect tolerance zone boundary.
 15. The methodaccording to claim 12, wherein: said receiving the patient inputcomprises detecting an acoustic signal indicating that the patient hasreached the side effect tolerance zone boundary.
 16. The methodaccording to claim 12, wherein: said receiving the patient inputcomprises detecting a motion signal with a motion sensor indicating thatthe patient has reached the side effect tolerance zone boundary.
 17. Themethod according to claim 1, further comprising: initiating an elevatedstimulation session at an elevated stimulation intensity for a firstperiod of time; and after the first period of time, initiating sustainedstimulation at a sustained stimulation intensity for a second period oftime, wherein the elevated stimulation intensity is greater than thesustained stimulation intensity.
 18. The method according to claim 17,wherein: the elevated stimulation intensity corresponds to a moderateside effect tolerance zone; and the sustained stimulation intensityproduces tolerable side effects.
 19. The method according to claim 17,wherein: the first period of time is less than one day; and the secondperiod of time is greater than one day.
 20. The method according toclaim 19, wherein: the first period of time is less than six hours; andthe second period of time is greater than one week.
 21. The methodaccording to claim 1, further comprising: receiving a session initiationinput to indicating an initiation time for titration sessions.
 22. Themethod according to claim 21, wherein: the session initiation inputindicates a time of day during which titration sessions are to beinitiated.
 23. The method according to claim 21, wherein: the receivingthe session initiation input comprises receiving a radio frequency (RF)signal from an external communications device.
 24. The method accordingto claim 21, wherein: the receiving the session initiation inputcomprises detecting a magnetic field.
 25. The method according to claim1, further comprising: in response to receiving a command from anexternal clinician programmer, initiating a training session comprisingactivating the IMD to deliver a stimulation signal of graduallyincreasing intensity; and receiving a control input from a patientdevice indicating the side effect tolerance zone boundary.
 26. Themethod according to claim 25, wherein: said receiving the control inputfrom the patient device comprises receiving a radio frequency (RF)signal from an external patient device, said wireless signal indicatingthat the patient has reached the side effect tolerance zone boundary.27. The method according to claim 25, wherein: said receiving thecontrol input from the patient device comprises detecting a magneticfield indicating that the patient has reached the side effect tolerancezone boundary.
 28. The method according to claim 25, further comprising:transmitting from the IMD to the external clinician programmerinformation regarding the stimulation signal intensity.
 29. The methodaccording to claim 25, further comprising: in response to receiving ahold command from the external clinician programmer, temporarily ceasingthe gradual increase of intensity of the stimulation signal.
 30. Themethod according to claim 25, further comprising: displaying on a userinterface of the external clinician programmer instructions forconducting the training session.
 31. The method according to claim 25,further comprising: in response to receiving a command from an externalclinician programmer, initiating a training session comprisingactivating the IMD to deliver a stimulation signal of graduallyincreasing intensity; and receiving a control input to proceed to asubsequent step in the training session.